The present invention relates to an ingestible pill platform for colon imaging, and more particularly, to an ingestible pill platform, designed to recognize its entry to the colon and designed to expand in the colon, for improved imaging of the colon walls.
The impact of cancer of the gastrointestinal tract is grave. In spite of enormous expenditures of financial and human resources, early detection of malignant tumors remains an unfulfilled medical goal. While it is known that a number of cancers are treatable if detected at an early stage, lack of reliable screening procedures results in their being undetected and untreated.
There are other gastrointestinal-tract disorders, which similarly require reliable screening and diagnostic procedures for early detection and treatment. These include, for example, irritable bowel syndrome, fluxional diarrhea, ulcerative colitis, collagenous colitis, microscopic colitis, lymphocytic colitis, inflammatory bowel disease, Crohn's disease, infectious diarrhea, ulcerative bowel disease, lactase deficiency, infectious diarrhea, amebiasis, and giardiasis.
A large number of techniques are available today for tissue characterization, for example, to determine the presence of abnormal tissue, such as cancerous or pre-cancerous tissue. Many of these may be used with miniature probes that may be inserted into a body lumen.
Tissue Characterization by Nuclear Imaging Nuclear-radiation imaging of radionuclide-labeled antibodies (Gamma Imaging): The use of radiolabeled immunoglobulin for tumor localization, by functional imaging, was shown to be possible in 1959 when Day et al. radiolabeled isolated antifibrin. (Day, E. O.; Planisek, J. A.; Pressman D: “Localization of Radioiodinated Rat Fibrinogen in Transplanted Rat Tumors”, J. Natl. Cancer. Inst. 0.23: 799-812, 1959). Since the work of Day et al, in 1959, an expanding number of monoclonal, antibodies have received FDA approval. Examples, applicable to gastrointestinal tract tumors, include the following:    1. CEA-Scan is a Tc99m-labeled monoclonal antibody fragment, which targets CEA—produced and shed by colorectal carcinoma cells. The use of anti-CEA, monoclonal antibody has been recommended as the only marker to estimate prognosis and response to therapy. Anti-CEA monoclonal antibody may also be labeled by other radioisotopes, for example, iodine isotopes. (Jessup J M. 1998, Tumor markers—prognostic and therapeutic implications for colorectal carcinoma, Surgical Oncology, 7: 139-151.)    2. In111 -Satumomab Pendetide (ONCOSCINT®) is designed to target TAG-72. TAG-72 is a mucin-like glycoprotein expressed in human colorectal, gastric, ovarian, breast and lung cancers. It is rarely expressed in normal human adult tissues. (Molinolo A; Simpson JF; et al. 1990, Enhanced tumor binding using immunohistochemical analyses by second generation anti-tumor-associated glycoprotein 72 monoclonal antibodies versus monoclonal antibody B72.3 in human tissue, Cancer Res. 50(4): 1291-8.)    3. Lipid-Associated Sialic Acid (LASA) is a tumor antigen, which for colorectal-carcinoma LASA, has a similar sensitivity as CEA but a greater specificity for differentiating between benign and malignant lesions. (Ebril K M, Jones J D, Klee G G. 1985, Use and limitations of serum total and lipid-bound sialic acid concentrations as markers for colorectal cancer, Cancer; 0.55:404-409.)    4. Matrix Metaloproteinase-7(MMP-7) is a proteins enzyme, believed to be involved in tumor invasion and metastasis. Its expression is elevated in tumor tissue compared to normal tissue and may be a potential marker for tumor aggressiveness and traditional staging. (Mori M, Barnard G F et al. 1995, Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinoma. Cancer; 75: 1516-1519.)
Additionally, pharmaceuticals may be used as markers for nonmalignant pathologies, such as gastrointestinal inflammations and infections. Examples include the following:    1. Ga67 citrate binds to transferrin and is used for detection of chronic inflammation. (Mettler F A, and Guiberteau M J, Eds. 1998, Inflammation and infection imaging. Essentials of nuclear medicine. Fourth edition. Pgs: 387-403.)    2. Nonspecific-polyclonal immunoglobulin G (IgG) may be labeled with both In111 or Tc99m, and has a potential to localize nonbacterial infections. (Mettler F A, and Guiberteau M J, ibid.)    3. Radio-labeled leukocytes, such as such as In111 oxine leukocytes and Tc99m HMPAO leukocytes are attracted to sites of inflammation, where they are activated by local chemotactic factors and pass through the endothelium into the soft tissue. Labeled leukocytes in the gastrointestinal tract are nonspecific and may indicate a number of pathologies, including Crohn's disease, ulcerative colitis; psudomembranous colitis, diverticulosis, various gastrointestinal infections, fistulas, ischemic or infracted bowel. (Mettler F A, and Guiberteau M J, ibid; Corstens F H; van der Meer J W. 1999. Nuclear medicine's role in infection and inflammation. Lancet; 354 (9180): 765-70.)
The particular choice of a radionuclide for labeling antibodies is dependent upon its nuclear properties, the physical half-life, the detection instruments' capabilities, the pharmacokinetics of the radiolabeled antibody, and the degree of difficulty of the labeling procedure. Examples of radionuclides used for labeling antibodies include Technetium Tc99m, Iodine I125, I123, I131, and I133, Indium In111, Gallium Ga67, thallium TI201, fluorine F18 and P32.
Nuclear-radiation imaging of radionuclide-labeled antibodies is a subject of continued development and study. Its advantage is that pathologies, which are embedded within a tissue or hidden by residue, may still be visible to the gamma camera, since the gamma rays penetrate the tissue or residue. In fact various means may be employed to calculate the depth of the pathology within the tissue, for example, based on the attenuation of photons of different energies, which are emitted from a same source, as taught by commonly owned U.S. patent application Ser. Nos. 10/616,307 and 10/616,301, both filed on Jul. 10, 2003, and both of whose disclosures are incorporated herein by reference, or by constructing an attenuation correction map for the functional image, based on a structural image, for example, of ultrasound, as taught by commonly owned PCT Patent application PCT/IL03/00917, filed on Nov. 4, 2003, whose disclosure is incorporated herein by reference.
A particular difficulty in using radionuclides is that blood-pool background radioactivity has caused ordinary scintigrams to prove difficult to interpret. Computer subtraction of radioactive blood-pool background radioactivity has been attempted to enhance imaging. Yet the ability to detect occult tumors has remained low.
Attempts to overcome the blood-pool background radioactivity are described, for example, in U.S. Pat. No. 4,782,840 to Martin, Jr., et al., entitled, “Method for locating, differentiating, and removing neoplasms,” U.S. Pat. No. 4,801,803 to Denen, et al., entitled, “Detector and localizer for low energy radiation emissions,” U.S. Pat. No. 5,151,598 to Denen, entitled, “Detector and localizer for low-energy radiation emissions,” U.S. Pat. No. 4,893,013 to Denen et al., entitled, “Detector and Localizer for Low Energy Radiation Emissions,” and U.S. Pat. No. 5,070,878 to Denen, entitled, “Detector and localizer for low energy radiation emissions,” and U.S. Pat. No. 6,259,095, to Boutun, et al., entitled, “System and apparatus for detecting and locating sources of radiation,” all of whose disclosures are incorporated herein by reference, which relate to the RIGS™. (RIGS is a registered trademark of Neoprobe Corporation of Dublin, Ohio), and to “NEOPROBE” instrument.
In spite of these advances, background radiation remains an obstacle that limits the probe sensitivity to occult tumors, and there are continued endeavors to minimize its effect.
Tissue Characterization by Ultrasonography: Ultrasonography is a medical imaging technique, using high frequency sound waves in the range of about 1 to 20 MHz and their echoes. The sound waves travel in the body and are reflected by interfaces between different types of tissues, such as between a healthy tissue and a denser cancerous tissue, or between a portion of a soft tissue and a bone. The ultrasound probe receives the reflected sound waves and the associated instrumentation calculates the distances from the probe to the reflecting boundaries.
The ultrasound probe includes a piezoelectric crystal, which produces an electric signal in response to a pressure pulse. The shape of the probe determines its field of view, and the frequency of the emitted sound determines the minimal detectable object size. Generally, the probes are designed to move across the surface of the body. However, some probes are designed to be inserted through body lumens, such as the vagina or the rectum, so as to get closer to the organ being examined.
Before the early 1970's ultrasound imaging systems were able to record only the strong echoes arising from the outlines of an organ, but not the low-level echoes of the internal structure. In 1972 a refined imaging mode was introduced called gray-scale display, in which the internal texture of many organs became visible. In consequence, ultrasound imaging became a useful tool for imaging tumors, for example, in the liver.
Contrast agents may be used in conjunction with ultrasound imaging, for example as taught by U.S. Pat. No. 6,280,704, to Schutt, et al., entitled, “Ultrasonic imaging system utilizing a long-persistence contrast agent,”whose disclosure is incorporated herein by reference.
Tissue Characterization by Electrical Impedance Imaging: Electrical impedance imaging relates to measuring the impedance between a point on the surface of the skin and some reference point on the body of a patient. Sometimes, a multi-element probe, formed as a sheet having an array of electrical contacts, is used for obtaining a two-dimensional impedance map of the tissue, for example, the breast. The two-dimensional impedance map may be used, possibly in conjunction with other data, such as mammography, for the detection of cancer.
Rajshekhar, V. (“Continuous impedance monitoring during CT-guided stereotactic surgery: relative value in cystic and solid-lesions,” Rajshekhar, V., British Journal of Neurosurgery, 1992, 6, 439-444) describes using an impedance probe with a single electrode to measure the impedance characteristics of lesions. The objective of the study was to use the measurements made in the lesions to determine the extent of the lesions and to localize the lesions more accurately. The probe was guided to the tumor by CT and four measurements were made within the lesion as the probe passed through the lesion. A biopsy of the lesion was performed using the outer sheath of the probe as a guide to position, after the probe itself was withdrawn.
Other work in impedance probes includes U.S. Pat. No. 4,458,694, to Sollish, et al., entitled, “Apparatus and method for detection of tumors in tissue,” U.S. Pat. No. 4,291,708 to Frei, et al., entitled, “Apparatus and method for detection of tumors in tissue,” and U.S. Pat. Nos. 6,308,097, 6,055,452 and 5,810,742, to Pearlman, A. L., entitled, “Tissue characterization based on impedance images and on impedance measurements,” all of whose disclosures are incorporated herein by reference.
Tissue Characterization by Optical Fluorescence Spectroscopy: When a sample of large molecules is irradiated, for example, by laser light, it will absorb radiation, and various levels will be excited. Some of the excited states will return back substantially to the previous state, by elastic scattering, and some energy will be lost in internal conversion, collisions and other loss mechanisms. However, some excited states will create fluorescent radiation, which, due to the distribution of states, will give a characteristic wavelength distribution.
Some tumor-marking agents give well-structured fluorescence spectra, when irradiated by laser light. In particular, hematoporphyrin; derivatives. (HPD), give a well-structured fluorescence spectrum, when excited in the Soret band around 405 rim. The fluorescence spectrum-shows typical peaks at about 630 and 690 nm, superimposed in practice on more unstructured tissue autofluorescence. Other useful tumor-marking agents are dihematoporphyrin ether/ester (DHE), hematoporphyrin (HP), polyhematoporphyrin ester (PHE), and tetrasulfonated phthalocyanine (TSPC), when irradiated at 337 nm (N2 laser).
U.S. Pat. No. 5,115,137, to Andersson-Engels, et al, entitled, “Diagnosis by means of fluorescent light emission from tissue,” whose disclosure is incorporated herein by reference, relates to improved detection of properties of tissue by means of induced fluorescence of large molecules. The tissue character may then be evaluated from the observed large-molecule spectra. According to U.S. Pat. No. 5,115,137, the spectrum for tonsil cancer is clearly different from normal mucosa, due to endogenous porphyrins.
U.S. Pat. No. 6,258,576, to Richards-Kortum, et al., entitled, “Diagnostic method and apparatus for cervical squamous intraepithelial lesions in vitro and in vivo using fluorescence spectroscopy,” whose disclosure is incorporated herein by reference, relates to the use of multiple illumination wavelengths in fluorescence spectroscopy for the diagnosis of cancer and precancer, for example, in the cervix. In this manner, it has been possible to (i) differentiate normal or inflamed tissue from squamous intraepithelial lesions (SILs) and (ii) differentiate high grade SILs from, non-high grade SILs. The detection may be performed in vitro or in vivo. Multivariate statistical analysis has been employed to reduce the number of fluorescence excitation-emission wavelength pairs needed to redevelop algorithms that demonstrate a minimum decrease in classification accuracy. For example, the method of the aforementioned patent may comprise illuminating a tissue sample, with electromagnetic radiation wavelengths of about 337 nm, 380 nm and 460 nm, to produce fluorescence; detecting a plurality of discrete emission wavelengths from the fluorescence; and calculating from the emission wavelengths a probability that the tissue sample belongs in particular tissue classification.
U.S. Patent Application 2003/01383786, to Hashimshony, entitled, “Method and apparatus for examining tissue for predefined target cells, particularly cancerous cells, and a probe useful for such method and apparatus,”whose disclosure is incorporated herein by reference, teaches a method apparatus and probe for examining tissue and characterizing its type according to measured changes in optical characteristics of the examined tissue. In a preferred embodiment of this method the tissue to be examined is subject to a contrast agent containing small particles of a physical element conjugated with a biological carrier selectively bindable to the target cells. Additionally, energy pulses are applied to the examined tissue, and the changes in impedance and/or the optical characteristics produced by the applied energy pulses are detected and utilized for determining the presence of the target cells in the examined tissue. Furthermore, in a preferred embodiment, the applied energy pulses include laser pulses, and the physical element conjugated with a biological carrier is a light-sensitive semiconductor having an impedance which substantially decrease in the presence of light. Moreover, the same probe used for detecting the targeted cells, may also be used for destroying the ‘cells’ so targeted.
Tissue Characterization by Optical Reflective Spectroscopy: The application optical reflectance spectroscopy for tissue characterization is described, for example, in http://www.sbsp-limb.nichd.nih.gov/html/spectroscopy.html, downloaded on Mar. 15, 2005, disclosing an optical reflectance spectroscopy (ORS) device for measuring the thickness of the epithelial layer, and an evaluation technique based on oblique angle reflectance spectroscopy, that allows assessment of the scattering and absorption properties of the epithelium and stroma, thus providing information on chronic oral epithelial tissue inflammation, which is considered a potential diagnostic precursor to oral cancer.
Additionally, Tomatis, A., et al, studied reflectance images of 43 pigmented lesions of the skin (18 melanomas, 17 common melanocytic naevi and eight dysplastic naevi). Reflectance images were acquired by a telespectrophotometric system and were analyzed in the spectral range from 420 to 1040 nm, to discriminate melanoma from benign melanocytic entities. Different evaluations were carried, out considering the whole spectrum, the visible and the near infrared. A total of 33 (76.7%) lesions were correctly diagnosed by the telespectrophotometric system, compared with 35 (81.4%) correct clinical diagnoses. Reflectance in the infrared band appears diagnostically relevant.
Tissue Characterization by Magnetic Resonance Imaging (MRI): Magnetic resonance imaging is based on the absorption and emission of energy in the radio frequency range of the electromagnetic spectrum, by nuclei having unpaired spins.
Conventional MRI is a large-apparatus, for whole body imaging, having:
i. a primary magnet, which produces the Bo field for the imaging procedure;
ii. gradient coils for producing a gradient in Bo;
iii. an RF coil, for producing the B1 magnetic field, necessary to rotate the spins by 90° or 180° and, for detecting the MRI signal; and
iv. a computer, for controlling the components of the MRI imager
Generally, the magnet is a large horizontal bore superconducting magnet, which provides a homogeneous magnetic field in an internal region within the magnet, A patient or object to be imaged is usually positioned in the homogeneous field region located in the central air gap for imaging. A typical gradient coil system comprises an anti-Helmholtz type of coil. These are two Parallel ring shaped coils, around the z axis. Current in each of the two coils flows in opposite directions creating a magnetic field gradient between the two coils.
The RF coil creates a B1 field, which rotates the net magnetization in a pulse sequence. The RF coils may be: 1) transmit and receive coils, 2) receive only coils, and 3) transmit only coils.
As described hereinabove, the MRI relies on a magnetic field in an internal region within the magnet. As such, it is unsuitable as a handheld probe or an endoscopic probe, because the tissue to be imaged has to be in the internal region of the imager,
However, U.S. Pat. No. 5,572,132, to Pulyer, et al., entitled, “MRI probe for external imaging,” whose disclosure is incorporated herein by reference, describes an MRI spectroscopic probe having an external background magnetic field B0 (as opposed to the internal background magnetic filed of the large horizontal bore superconducting magnet.). Thus, an MRI catheter for endoscopical imaging of tissue of the artery wall, rectum, urinal tract, intestine, esophagus, nasal passages, vagina and other biomedical applications may be constructed. The probe comprises (i) a miniature primary magnet having a longitudinal axis and an external surface extending in the axial direction, and (ii) a RF coil surrounding and proximal to said surface. The primary magnet is structured and configured to provide a symmetrical, preferably cylindrically shaped, homogeneous field region external to the surface of the magnet. The RF coil receives NMR signals from excited nuclei. For imaging, one or more gradient coils are provided to spatially encode the nuclear spins of nuclei excited by an RF coil, which may be the same coil used for receiving NMR signals or another RF coil.
Contrast agents may be used in conjunction with MRI For example, U.S. Pat. No. 6,315,981 to Unger, entitled, “Gas filled microspheres as magnetic-resonance imaging contrast agents,” whose disclosure is incorporated herein by reference; describes the use of gas filled microspheres as contrast agents for MRI; Unger further describes how gas can be used in combination with polymer compositions and possibly also with paramagnetic, superparamagnetic, and liquid fluorocarbon compounds as MRI contrast agents. It is further shown how: the gas stabilized by polymers would function as an effective susceptibility contrast agent to decrease signal intensity on T2 weighted images; and that such systems are particularly effective for use as gastrointestinal MRI contrast media Additionally, when MRI contrast agents are tied up to antibodies, the MRI may be used as a functional imaging technique. The MRI contrast agent may be a solution of Gd-dtpa, prepared for injection.
Tissue Characterization by Temperature Imaging: Temperature Imaging for locating and detecting neoplastic tissue has been known, since the 1950's, when it was discovered that the surface temperature of skin in the area of a malignant tumor exhibited a higher temperature than that expected of healthy tissue. Thus, by measuring body skin temperatures, it became possible to screen for the existence of abnormal body activity such as cancerous tumor growth. With the development of liquid crystals and methods of forming temperature responsive chemical substrates, contact thermometry became a reality along with its use in medical applications. Devices employing contact thermometry could sense and display temperature changes through indicators, which changed colors, either permanently or temporarily, when placed in direct physical contact with a surface such as skin, reflecting a temperature at or near the point of contact. An abnormal reading would alert a user to the need for closer, more detailed examination of the region in question. However, the art in this area has been directed primarily at sensing and displaying temperatures on exterior skin surfaces.
U.S. Pat. No. 6,135,968, to Brounstein, entitled, “Differential temperature measuring device and method”, whose disclosure is incorporated herein by reference, describes a device and method for sensing temperatures at internal body locations non-surgically accessible only through body orifices. The device is particularly useful in medical applications such as screening for cancer and other abnomial biological activity signaled by an increase in temperature at a selected site.
Ingestible Pills: Ingestible radio pills, which are ingestible capsules containing a transmitter are known. In 1964 research at Heidelberg University developed a pill for monitoring pH of the gastrointestinal tract. (Noller, H. G., “The Heidelberg Capsule Used For the Diagnosis of Pepic Diseases”, Aerospace Medicine, February, 1964, pp. 15-117.)
U.S. Pat. No. 5,604,531; to Iddan, et al., entitled, “In vivo video camera system,” whose, disclosure is incorporated herein by reference, describes a video camera system, encapsulated within an ingestible pill, arranged to pass through the entire digestive tract, operating as an autonomous video endoscope. The ingestible pill includes a camera system and an optical system for imaging an area of interest onto the camera system, and a transmitter, which relays the video output of the camera system to an extracorporeal reception system. A light source is located within a borehole of the optical system.
Similarly, U.S. Patent Application 20010035902, to Iddan, G. J., et al., entitled, “Device and system for in vivo imaging,” whose disclosure is incorporated herein by reference, describes a system and method for obtaining in vivo images. The system contains an imaging system and an ultra low-power radio frequency transmitter for transmitting signals from the CMOS imaging camera to a receiving system located outside a patient. The imaging system includes at least one CMOS imaging camera, at least one illumination source for illuminating an in vivo site and an optical system for imaging the in vivo site onto the CMOS imaging camera.
U.S. Pat. No. 6,324,418, to Crowley, et al., entitled, “Portable tissue spectroscopy apparatus and method,.” whose disclosure is incorporated herein by reference, describes a portable tissue spectroscopy apparatus including at least one light source, at least one light detector, a power source and a controller module, all disposed inside a housing that is insertable inside a body. The housing may be in the form of a hand-holdable probe or in the form of a capsule that can be swallowed or implanted in the body. The probe further includes a display mounted at a proximal end of the housing for displaying tissue characteristics. The capsule further includes a transmitter mounted inside the capsule and a receiver placed outside the body for transmitting signals representative of tissue characteristics to a remote receiver.
The capsule includes one or more light emitters and one or more light detectors. The light detectors may be located in various places within the housing for detecting spectroscopic properties from various tissues near the capsule. The capsule may further include other types of emitters and sensors. The additional emitters and sensors, for example, can relate to electromagnetic radiation; pressure, temperature, x-ray radiation and/or heat. In one embodiment, the capsule further comprises an acoustic transmitter and a receiver for measuring flow of fluid or for detecting echo location of the capsule. In another embodiment, the capsule further includes diagnostic sensors such as monitoring electrodes, pressure sensors and temperature sensors.
Methods of tracking ingestible devices, such as radio pills, are known. U.S. Pat. No. 5,279,607, to Schentag, et al., entitled, “Telemetry capsule and process,” and U.S. Pat. No. 5,395,366, to D'Andrea et al. entitled, “Sampling capsule and process,” described hereinabove, include extracorporeal apparatus having a plurality of antennae, used to determine the geographic position of the capsule within the gastrointestinal tract. For example, at least three antennae, located at different distances from the point source, and dedicated algorithms may be used to determine the precise location of the capsule, at any time.
U.S. Pat. No. 6,082,366 to Andrii et al., entitled, “Method and arrangement for determining the position of a marker in an organic cavity,” whose disclosure is incorporated herein by reference, describe a method for pinpointing a marker such as an ingestible capsule. The method requires that the patient be positioned within a magnetic field, for example, as used for MRI imaging.
Commonly owned U.S. Patent Application 20030139661, to Kimchy et al., entitled, “Ingestible pill,” whose disclosure is incorporated herein by reference describes an ingestible device, adapted to travel in the gastrointestinal tract and perform a diagnostic image of tissue therein. The diagnostic image may comprise diagnostic information as a function of time, or diagnostic information as a function of distance traveled within the gastrointestinal tract. Specifically, the ingestible device may be arranged to perform a diagnostic image of nuclear radiation of a radiopharmaceutical, scintillation of a scintillation liquid, responsive to nuclear radiation of a radiopharmaceutical, optical fluorescence of a fluorescing-pharmaceutical or of bare gastrointestinal-tract tissue, infrared radiation of the gastrointestinal-tract tissue, temperature-differences along the gastrointestinal-tract, impedance, ultrasound reflection, magnetic resonance, and a combination thereof. The ingestible device may be adapted for general screening of a large population, on the one hand, and for specific diagnoses of suspected pathologies, on the other.
Additionally, commonly owned U.S. Patent Application. 20040054278, to Kimchy, et al., entitled “Ingestible device,” describes a device, adapted to travel in the gastrointestinal tract and perform a diagnostic image of tissue therein. The diagnostic image may comprise diagnostic information as a function of time, or diagnostic information as a function of distance traveled within the gastrointestinal tract. An imaging method by depth calculations is provided, based on the attenuation of photons of different energies, which are emitted from the same source, coupled with position monitoring.
Notwithstanding the high level of sophistication of the aforementioned systems, gastrointestinal pathologies, and particularly, occult tumors have remained elusive in medical diagnosis. There is thus a widely recognized need for, and it would be highly advantageous to have, a device and method for detecting pathologies in the gastrointestinal tract devoid of the above limitations.